Antibiotic resistance is a worldwide problem (J. Med. Chem., 1996;39:3853) with catastrophic potential (Southern Med. J., 1995;88:797). In 1995, the American Society of Microbiology Task Force issued a report defining the resistance problem and calling for new antibacterial agents with novel structures or mechanisms to offer alternatives to existing therapeutic choices.
The quinolone antibacterials as exemplified by ciprofloxacin 1 represent a significant addition to the therapeutic options currently available. The quinolones are potent, inhibit gram positive and gram negative bacteria, and may be administered orally or IV. The quinolones also have several significant side effects (J. Antimicrob. Chemother., 1994;33:685), and significant resistance has been frequently noted (Gootz, Medicinal Research, 1996; Rev. 16:433). ##STR1##
The quinolones have a distinct structure activity relationship which has been defined by several thousands of analogs prepared over the last 30 years (Progress in Drug Research, Editor S. Mitsuhashi, 1992;38:11-147). In the quinolone SAR, it is well-established that the N.sub.1 group with the C.sub.3 -carboxyl and the C.sub.4 carbonyl are essential for activity and that any substituents at C.sub.2 detract from activity (J. Antimicrob. Chemother., 1994;33:685 and Gootz, supra., 1996). It is also well-established that R.sub.6 is ideally fluorine, and that R.sub.7 is a nitrogen containing heterocycle. R.sub.1 is ideally a small alkyl, cycloalkyl, or a phenyl group. ##STR2##
The quinolones inhibit bacterial growth by inhibition of DNA gyrase and Topoisomerase IV (Gootz, supra., 1996). The gyrase interaction appears to rely on the N.sub.1 -C.sub.4 -carbonyl-C.sub.3 -carboxyl relationship.
Attempts to design novel quinolone mimics have focused on the N.sub.1 -C.sub.4 -carbonyl-C.sub.3 -carboxyl relationship. Compounds of type 3 were designed to keep an all planar relationship and to have the NH of the isothiazole ring be as acidic as the quinolone CO.sub.2 H (Chu, Drugs Exptl. Clin. Res., 1990;16:215). While maintaining excellent quinolone activity, these compounds also showed antitumor and mammalian topoisomerase activity (Drugs of the Future, 1992;17:1101) which is undesired in an antibacterial agent. ##STR3##
Several publications (U.S. Pat. No. 5,283,248; J. Med. Chem., 1992;35:1358; Antimicrob. Agents Chemother:, 1995;39:163) cite compounds of type 4 as having antibacterial activity and inhibition of DNA gyrase. In compounds 4, the relationship of the N.sub.1 to the C.sub.4 carbonyl has been skewed. Compounds of type 4 were also ineffective against bacteria that were quinolone resistant. ##STR4##
Compounds of type 5 have also been revealed as quinolone mimics (JP 4,091,090 3/92; Interscience Conference on Antimicrobial Agents and Chemotherapy 1991, Abstract 1494). These agents were reported to possess antibacterial and gyrase activity. While the ideal N.sub.1 -C.sub.4 -carbonyl relationship is maintained in 5, the C.sub.2 region where substitution is undesirable in the quinolones is filled with a major part of the ring. None of the quinolone mimics 3-5 exactly mimics the quinolone parent structure because all contain an extra third ring used to deliver the acidic H group required for activity.
WO 96/04288 describes a series of benzoheterocycles 6 which are glycine receptor antagonists. X, Y, and Z are chosen to provide hydrogen bond acceptor and donator groups. Among the compounds depicted are some N-hydroxyquinazoline-2,4-diones 7, where R.sub.1 -R.sub.4 may be hydroxy, amino, nitro, a variety of alkyls, esters, and amides. In all cases, the substituent on N.sub.1 is hydrogen. None of the substituents R.sub.1 -R.sub.4 are nitrogen containing heterocycles. No antibacterial activity is revealed. ##STR5##
U.S. Pat. No. 5,155,110 (10/92) reveals certain N.sub.1 -aryl-N-hydroxy-quinazoline-2,4-diones 8 as cyclooxygenase and lipoxygenase inhibitors. R may be halo, cyano, hydroxy, alkoxy, and substituted amino. Amino heterocycles are not included in R, and no antibacterial activity is described. ##STR6##